Fat emulsion is a kind of emulsion having very fine particles of fat homogeneously dispersed in water. Especially, an intravenous fat emulsion has been developed for supplying calories to the patients who cannot take them orally and is now commercially available [cf. "the fundamentals and preparation of high-calorie transfusion solution": second press; p. 74-81, (1981); Sigehiko Shimada, YAKUJI NIPPO (Japan)]. Usually, fat emulsion means such intravenous emulsions.
This type of fat emulsion is normally prepared by heating the fat component such as soybean, cotton seed or safflower oil along with an emulsifier such as yolk phospholipid, lecithin or soybean lecithin, and other additives, roughly emulsifying them together with a needed amount of water by means of a homomixer, then finely emulsifying using a jet-type high-pressure homogenizer, and sterilizing with high-pressure steam.
The fat emulsion thus prepared is a homogeneous dispersion of oil-drop particles (of less than 1 micrometer average particle size) coated with an emulsifier on their surface in water. The oil-drop particles coated with an emulsifier on their surface is defined as "fat emulsion particles" here.
In recent years, a variety of trials have been made to develop more reasonable pharmacotherapy with increased efficacy and safety of medicinal substances by controlling the release of the substance from the preparation, preventing the substance from being inactivated in vivo, controlling the distribution of the substance in the living body, or prolonging the retention at the affected part. One of these trials is to develop a satisfactory carrier in which the pharmaceutical substance in the preparation is embedded. In this method, the behavior or efficacy of the pharmaceutical substance largely depend on the absorption, distribution, metabolism, and excretion of the carrier in vivo, differing from a usual preparation in which the pharmaceutical substance is released from the preparation, absorbed, distributed, metabolized and excreted alone in vivo.
The meaning of "a pharmaceutical substance is embedded in a carrier" is defined as follows:
A part or all of the molecules of the pharmaceutical substance constituting the preparation along with the carrier and others such as an excipinet are individually included in the carrier partially or entirely in their molecular bodies.
One of the examples of the entire part of one molecule of the pharmaceutical substance embedded in the carrier is the case in which the pharmaceutical substance is dissolved in the carrier, while an example of one molecule partially included is the case where a part of the molecule exists in the carrier and the rest is exposed to the outside.
Liposome of doubled lipid membrane has been known as such a carrier for a pharmaceutical substance.
Recently, however, trials of utilizing the above-stated fat emulsion particles as a carrier for embedding the pharmaceutical substance have been reported. They describe that the pharmaceutical substance-containing fat emulsion prepared by emulsifying the pharmaceutical substance along with fat and emulsifier prolonged the half-life in vivo of the substance compared with the case where the substance was given without the fat emulsion, and transferred the substance to the target site with selectivity increased.
As examples, are cited a steroid-fat emulsion [Japanese Patent, Laid-open No. 57-16,818 (1982)], a biphenylpropionic acid derivative-fat emulsion [Japanese Patent, Laid-open No. 60-16,923 (1985)] and a prostaglandin E.sub.1 -fat emulsion [Japanese Patent, Laid-open No. 58-222,014 (1983)]. The reason why the behavior in vivo of the pharmaceutical substance-containing fat emulsion differs from that of a preparation without the fat emulsion (such as a solution solubilized using a surface active agent) is thought that the pharmaceutical substance is embedded in the fat emulsion particles.
The process for preparation of such a pharmaceutical substance-containing fat emulsion is almost the same as that for preparation of the above-stated fat emulsion. In other words, a pharmaceutical substance to be embedded is dissolved in a specific amount of the oil component, mixed with an emulsifier and other additives, heated, then roughly emulsified along with a needed amount of water using a homomixer, finely emulsified into fine particles of less than 1 micrometer average particle size using a jet-type high-pressure homogenizer, and sterilized with high-pressure steam, after sealed in vessels.
The pharmaceutical substance-containing fat emulsion which is prepared by this method is very useful in medicinal therapy, but has several defects.
The first thing is that the pharmaceutical substance-containing fat emulsion cannot be stored for a long period of time, in case that the pharmaceutical substance is unstable in the fat emulsion. A countermeasure against the defect is, for example, to remove the components which makes the pharmaceutical substance unstable or to add an additive which stabilizes the substance. A former example is a prostaglandin fat emulsion which is stabilized by removing phosphatidyl ethanolamine from the phospholipid [Japanese Patent, Laid-open No. 60-149,524 (1985)]. This method is not, however, the universal one which can stabilize a number of medicines, because the main factors for stabilization are different depending on individual medicinal substances. Therefore, such a pharmaceutical preparation has been desired, as the pharmaceutical substance unstable can be applied in the stabilized form where the substance is embedded in the fat emulsion particles.
The second matter is that there are some pharmaceutical substance-containing fat emulsions which cannot be prepared by the above-stated method. For example, a jet-type high-pressure homogenizer is used in the method, and medicinal substances which explode by a shock cannot be made into the corresponding pharmaceutical substance-containing fat emulsions. Additionally, injection preparations require the high-pressure steam sterilization, but thermally sensible or volatile medicinal substances decompose or dissipate during the steam sterilization. In other words, the medicinal substances which is sensible to heat and highly volatile cannot be made into said pharmaceutical substance-containing fat emulsions.
Accordingly, the development has been desired on the preparations which enable the medicinal substances unstable to heat, shock or the like or highly volatile, to be applied by embedding them into the fat emulsion particles.
The present inventors have made intense investigation on the methods for preparing pharmaceutical substance-containing fat emulsions by mixing a fat emulsion with a pharmaceutical substance composition. Since the fat emulsion is a dispersion of oil or oil particles covered with a surface active agent on their surfaces, the inventors have thought that the pharmaceutical substance is taken into the fat emulsion particles according to the distribution coefficient between water and soybean oil, when the pharmaceutical substance composition is mixed with the oil emulsion.
If a pharmaceutical substance-containing fat emulsion can be prepared by mixing a pharmaceutical substance composition with a fat emulsion, the composition can avoid from the processes of the emulsification by means of a high-pressure jet type homogenizer and/or the sterilization with high-pressure steam. Additionally, if such a kit is provided, as a pharmaceutical substance-containing fat emulsion can be prepared by mixing the pharmaceutical substance composition with the fat emulsion, immediately before the preparation is applied, the stability of the pharmaceutical substance in the fat emulsion offers no longer problems.
Following prior arts have been known on the methods for preparation of such pharmaceutical substance-containing fat emulsions:
Fortner et al. described a method of mixing an anhydrous alcohol solution of an insoluble nitrosourea carcinostatic agent with a fat emulsion to prepare a fat emulsion containing the carcinostatic agent (cf. C. L. Fortner et al., Am. J. Hosp. Pharm. (1975) 32, 582-584).
El-Sayed et al disclosed a method for preparation of a fat emulsion containing a water-insoluble carbamic acid derivative, a carcinostatic agent, by dissolving the agent in a dimethylacetamide-cremophor.RTM. mixture, and mixing the solution with a fat emulsion(cf. A. A. Fl-Sayed et al., International Journal of Pharmaceutics, 13, (1983), 303-312).
It has been found, however, by the present inventors, that, when an anhydrous alcohol or a dimethylacetamide-cremophor.RTM. mixture is mixed with a fat emulsion in order to prepare a fat emulsion containing a sufficiently needed amount of a pharmaceutical substance for treatment, bubbles are formed in the emulsion, and the use of such pharmaceutical substance-containing fat emulsion as an injection is not undesirable from a safety point of view.
Consequently, it has been desired that a pharmaceutical substance-containing fat emulsion can be prepared, as the fat emulsion is kept stable, and solvents safe for medicinal substances will be found.